{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T05:48:19Z","timestamp":1780465699862,"version":"3.54.1"},"reference-count":52,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T00:00:00Z","timestamp":1771113600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T00:00:00Z","timestamp":1771113600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM145845"],"award-info":[{"award-number":["R01GM145845"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2026,4,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    We disclose an efficient transformation of the relatively common pyrroloiminoquinone discorhabdin alkaloids from Alaskan\n                    <jats:italic>Latrunculia<\/jats:italic>\n                    spp. to the complex ring system of aleutianamine by an acid catalyzed process that mimics the proposed endogenous genesis from 3\u2010dihydrodienyl discorhabdin precursors. The azepine ring system is formed by a concerted 1,2\u2010alkyl shift of a proposed thiocarbenium\u2010iminium dication and this mechanism is supported by extensive density functional theory (DFT) analysis. Additional in vitro biological data further supports the aleutianamines as novel and highly potent inhibitors of multidrug resistant cancer lines exemplified further with cytotoxicity toward chemotherapy resistant chromophobe renal cell carcinoma (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u00a0=\u00a0130\u00a0nM). This report provides a key transformation that allows the incorporation of either synthetic or biosynthetic starting materials leading to the generation of the aleutianamine complex ring system in just a single step from the discorhabdin ring system.\n                  <\/jats:p>","DOI":"10.1002\/anie.7864883","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T05:39:31Z","timestamp":1771220371000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["On the Discorhabdins Leading to the Aleutianamine Ring System: A One\u2010Step in Situ Transformation Characterized Through Computational and Experimental Studies and Its Implications on Biosynthesis, Synthesis, and Pharmacology"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1318-4438","authenticated-orcid":false,"given":"Cody F.","family":"Dickinson","sequence":"first","affiliation":[{"name":"Department of Drug Discovery &amp; Biomedical Sciences Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhay","family":"Potluri","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology University of California Davis  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison M.","family":"Bland","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel M.","family":"Flipse","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Hawaii at Manoa  Honolulu Hawaii USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George S.","family":"Hanna","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan T.","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith D.","family":"Robertson","sequence":"additional","affiliation":[{"name":"Department of Molecular Pharmacology and Experimental Therapeutics Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thai H.","family":"Ho","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology Hollings Cancer Center Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Sprague","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald R.","family":"Hoff","sequence":"additional","affiliation":[{"name":"Resource Assessment and Conservation Division Alaska Fisheries Science Center National Marine Fisheries Service National Oceanic and Atmospheric Administration  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert P.","family":"Stone","sequence":"additional","affiliation":[{"name":"Auke Bay Laboratories Alaska Fisheries Science Center National Marine Fisheries Service National Oceanic and Atmospheric Administration  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus A.","family":"Tius","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Hawaii at Manoa  Honolulu Hawaii USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2992-8844","authenticated-orcid":false,"given":"Dean J.","family":"Tantillo","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology University of California Davis  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3798-4002","authenticated-orcid":false,"given":"Mark T.","family":"Hamann","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery &amp; Biomedical Sciences Medical University of South Carolina  Charleston South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,2,15]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/md9112423"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmars.2014.00054"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c10212"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c12946"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c06578"},{"key":"e_1_2_6_7_1","article-title":"Optimized Biomimetic Syntheses of Discorhabdin B and Aleutianamine Drives a Deeper Exploration of Their Anticancer Activities","author":"Magann N.","year":"2025","journal-title":"ChemRxiv"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200390115"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.00454\u201008"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1025c18350"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.2174\/1381612033455297"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo00252a052"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo00376a096"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr100435g"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)96664-4"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0040\u20104039(96)01560\u20102"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/np50126a008"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/md15040098"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27248724"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c11897"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/np50124a020"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/np000220q"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/md16070241"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00227\u2010003\u20101109\u20105"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja205655w"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1025c15504"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200804890"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200804107"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b11403"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jnatprod.1025c01094"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/md21090474"},{"key":"e_1_2_6_32_1","unstructured":"This number is based on the reported mass isolated and accounted for by the reported %composition."},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo00105a047"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.11646\/zootaxa.4121.1.1"},{"key":"e_1_2_6_35_1","unstructured":"These organisms are no longer viable after recovery from depth and provide a unique source for investigations."},{"key":"e_1_2_6_36_1","unstructured":"Careful extraction and processing (i.e. avoidance of heat) revealed aleutianamine is present from the outset and not simply an artifact of isolation."},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol400294v"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/np900281r"},{"key":"e_1_2_6_39_1","unstructured":"Isolated as a constant mass hydrate 22%\u00a0wt\/wt as determined by QNMR; this is equivalent to 7.7\u00a0mg of aleutianamine."},{"key":"e_1_2_6_40_1","unstructured":"The largest production prior to this work was the result of a total synthesis by Vanderwal which reported production of 2.7\u00a0mg of aleutianamine TFA salt. See the supporting information of reference 6."},{"key":"e_1_2_6_41_1","unstructured":"The complete sponge material is derived from a survey of numerous islands in the archipelgao. We processed the material by first defatting prior to an ethanol extraction. For information on the haul and catch data of the NOAA Alaska Groundfish Survey please visit https:\/\/www.fisheries.noaa.gov\/foss\/f?p=215:28:1560460427822."},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010020\u20100933\u20106"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol060125u"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040\u20104039(01)01130\u20103"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol016408y"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo5007416"},{"key":"e_1_2_6_47_1","unstructured":"See SI for details."},{"key":"e_1_2_6_48_1","unstructured":"No reaction occurs at room temperature (TLC). See the SI for a DFT reaction mechanistic analysis of the rearrangement of 3\u2010DHDC."},{"key":"e_1_2_6_49_1","unstructured":"No reaction was observed (TLC) upon addition of <1 equiv. of bistriflimide. Presumably bistriflimide first protonates trifluoroacetate to trifluoroacetic acid and >1 equiv. of acid initiates the rearrangement."},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.07.006"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388\u2010025\u201003562\u20102"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.MCT\u201019\u20100233"},{"key":"e_1_2_6_53_1","unstructured":"The fluorometric Cell\u2010Titer Blue Assay (Promega) was used."}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.7864883","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.7864883","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.7864883","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T13:10:44Z","timestamp":1776777044000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.7864883"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,15]]},"references-count":52,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2026,4,20]]}},"alternative-id":["10.1002\/anie.7864883"],"URL":"https:\/\/doi.org\/10.1002\/anie.7864883","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,15]]},"assertion":[{"value":"2025-12-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e7864883"}}